The present invention relates to a novel amidine compound having a blood coagulation factor Xa inhibitory activity. The present invention also relates to a pharmaceutical composition, a factor Xa inhibitor and a therapeutic agent for the diseases caused by blood coagulation or thrombus, which comprises this compound.
One of the etiologies of thrombosis, such as unstable angina, deep vein thrombosis and disseminated intravascular coagulation (DIC), is promotion of blood coagulation. For the prophylaxis and treatment of thrombus, heparin and warfarin have been conventionally used. Heparin acts on antithrombin III (ATIII) to indirectly inhibit the coagulation system and, therefore, may show a weak action on arterial thrombus. Heparin is associated with generation of an antibody against platelet factor (PF4), which promotes coagulation in some patients, and a propensity toward hemorrhage as a side effect. Warfarin requires longer time for the expression of the drug effect and is not necessarily an easy and safe drug. Under the circumstances, a new anticoagulant is desired to overcome these problems.
The factor X is a glycoprotein having a molecular weight of 58,000, and in an intrinsic pathway, the factor X is activated on a phospholipid membrane in the presence of a factor IXa/factor VIIIa/Ca2+ complex and becomes factor Xa. In the coagulation system called extrinsic pathway, factor X is activated by factor VIIa in the presence of a tissue factor and becomes factor Xa. The factor Xa generated in the both pathways activates prothrombin to give thrombin. The generated thrombin further activates the upstream of this cascade to produce a large amount of thrombin. Consequently, fibrinogen becomes fibrin and coagulation of blood occurs.
Inasmuch as the blood coagulation system is an amplification reaction, inhibition of generation of thrombin in the early stage is considered to be more efficient than direct inhibition of the activity of the generated thrombin. In addition, since factor Xa is the confluence of intrinsic and extrinsic coagulation pathways, inhibition of factor Xa is considered to be extremely effective. Some reports have documented that low molecular weight heparin showed a lower tendency of bleeding than heparin in clinical applications, and in a test using baboon (Thrombosis and Haemostas, 74, 464 (1995)), it was found that inhibition of factor Xa rather than thrombin showed less tendency of bleeding. Therefore, a factor Xa inhibitor has a potential of showing antithrombus effect without influencing the bleeding time observed in the use of conventional anticoagulants.
As a factor Xa inhibitor, WO97/08165 discloses a compound of the formula 
wherein R1, R2 and R3 are each hydrogen atom, hydroxy, halogen atom, hydroxyalkyl, alkyl, alkenyl, alkynyl, alkoxy, aralkyloxy, alkenyloxy, alkynyloxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkenyloxycarbonylalkyl or alkynyloxycarbonylalkyl, A is alkylene optionally substituted by hydroxy, carboxy, alkoxycarbonyl or halogen atom, X is a bond, alkylene or alkyleneoxy, Y is a single bond, chalcogen atom or CO, Z is a saturated or unsaturated optionally substituted hetero ring or carbon ring, optionally substituted amino, hydroxy, carboxy, alkoxycarbonyl or alkyl, n is an integer of 1 or 2, and m is an integer of 0 to 4. In addition, Japanese Patent Unexamined Publication No. 5-208946 (U.S. Pat. No. 5,620,991, EP No. 540051) discloses a compound of the formula 
wherein R1 is hydrogen atom or lower alkoxy, R2 is hydrogen atom, lower alkyl, lower alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl, R3 is hydrogen atom, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, carboxyalkoxy or alkoxycarbonylalkoxy, R4 is hydrogen atom, hydroxy, lower alkyl or lower alkoxy, n is an integer of 0 or 1, A is C1-C4 alkylene optionally substituted by 1 or 2 substituents from hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl and alkoxycarbonylalkyl, X is a single bond, oxygen atom, sulfur atom or carbonyl, Y is optionally substituted saturated or unsaturated 5 or 6-membered heterocyclic group or cyclic hydrocarbon group, optionally substituted amino or optionally substituted aminoalkyl, and a group of the formula 
is selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl. Furthermore, WO96/16940 discloses a compound of the formula 
wherein R1 is hydrogen atom or a group of the formula xe2x80x94Axe2x80x94Wxe2x80x94R4 wherein A is a group of the formula 
or xe2x80x94SO2xe2x80x94 wherein X2 is oxygen atom or sulfur atom, and W is a single bond or xe2x80x94NR5xe2x80x94, R4 is hydroxy, lower alkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, with the proviso that when W is a group of the formula xe2x80x94NR5xe2x80x94, R4 may be hydrogen atom but is not hydroxy or lower alkoxy; wherein R5 is hydrogen atom, carbamoyl, lower alkoxycarbonyl, mono- or di(lower)alkylaminocarbonyl, lower alkylsulfonyl, mono- or di(lower)alkylaminothiocarbonyl, optionally substituted lower alkyl or optionally substituted lower alkanoyl; R2 is lower alkyl; R3 is hydrogen atom, halogen atom, carboxy, amino, cyano, nitro, hydroxy, lower alkoxy, lower alkyl or lower alkoxycarbonyl; B is lower alkylene or carbonyl; and n is an integer of 0 or 1.
The present invention aims at providing a novel compound useful as a factor Xa inhibitor. The present invention also aims at providing a novel factor Xa inhibitor.
In view of the above situation, the present inventors conducted intensive studies in an attempt to find a compound useful as a factor Xa inhibitor and found the amidine compound of the following formula [I]. They have further found that the compound can be a superior factor Xa inhibitor and completed the present invention.
The compound of the present invention specifically inhibits blood coagulation factor Xa and shows strong anticoagulation action. Therefore, the compound is useful as an agent for the prophylaxis and/or treatment of various diseases caused by blood coagulation or thrombus, namely, cerebrovascular diseases such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemia attack (TIA), subarchnoid hemorrhage and the like; ischemic heart diseases such as acute or chronic myocardial infarction, unstable angina, coronary thrombosis and the like; pulmonary vascular diseases such as pulmonary infarction, pulmonary embolism and the like; and diseases caused by various vascular disorders such as peripheral arterial embolism, deep vein thrombosis, disseminated intravascular coagulation, thrombosis after surgery of artificial blood vessels or replacement of artificial valve, reocclusion or restenosis after coronary bypass, reocclusion or restenosis after recanalization such as percutaneous transluminal coronary angioplasty (PTCA), percutaneous transluminal coronary recanalization (PTCR) and the like, thrombosis due to extracorporeal circulation and the like, glomerulonephritis, nephrotic syndrome, diabetic retinopathy, arteriosclerotic obliteration, Buerger disease, tumor thrombosis, thrombus by atrial fibrillation, and the like.
As is evident from Experimental Example 2 to be mentioned later, since the compound of the present invention does not have inhibitory activity against thrombin, namely, factor IIa (FIIa), hemorrhage as a side effect is considered to be noticeably less. Experimental Examples 6 and 7 to be mentioned later reveal striking factor Xa inhibitory effect by oral administration.
There is also a finding that factor Xa is involved in the growth of influenza virus (Japanese Patent Unexamined Publication No.6-227971). Thus, the compound of the present invention is expected to be useful for the prophylaxis and/or treatment of influenza.
The present invention relates to a compound of the following formula [I], which is useful as a factor Xa inhibitor. In addition, the present invention relates to a factor Xa inhibitory agent containing a compound of the following formula [I] or a salt thereof or a prodrug thereof as an active ingredient. More particularly, the present invention provides the following (1)-(23).
(1) An amidine compound of the formula [I]
wherein
R is a group of the formula 
xe2x80x83wherein
R4 is hydrogen atom, hydroxy group, lower alkyl group, lower alkoxy group or halogen atom,
R5 is hydrogen atom, cyano group, carboxy group or lower alkoxycarbonyl group,
R6 is hydrogen atom, cycloalkyl group, hydroxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group
wherein said aralkyloxycarbonyl group is optionally substituted by halogen atom, nitro group, alkyl group, alkoxy group or trifluoromethyl group,
nitro group, amino group, lower alkylamino group, di(lower)alkylamino group, aryl group, heteroaryl group
wherein said aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from lower alkyl group, hydroxy group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group,
5- to 7-membered saturated heterocycle having at least one nitrogen atom wherein said saturated heterocycle is optionally substituted by lower alkyl group, acyl group, di(lower)alkylamino(power)alkanoyl group or imidoyl group or 
xe2x80x83wherein Ak is lower alkyl group and Hal is halogen atom,
X2 is oxygen atom, sulfur atom, xe2x80x94SO2xe2x80x94, xe2x80x94SO2NHxe2x80x94 or a single bond,
X3 is xe2x80x94(CH2)mxe2x80x94 wherein m is 0 or an integer of 1 to 3,
X4 is xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90NH)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CSNHxe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94(CH2)rCONHxe2x80x94, xe2x80x94(CH2)rCH(OH)xe2x80x94, 
xe2x80x83wherein r is 0 or an integer of 1 to 3,
or a single bond,
X5 is alkylene group having 1 to 6 carbon atoms, alkenylene group having 2 to 6 carbon atoms, or a single bond,
R7 is hydrogen atom, lower alkyl group or 
xe2x80x83wherein R9 is oxygen atom, sulfur atom, NH, NR11 
wherein R11 is lower alkyl group, aralkyl group wherein said aralkyl group is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, haloalkyl group, cyano group, nitro group, amino group and acyloxy group,
or hydroxy group,
and R10 is lower alkyl group, lower alkoxy group, amino group, lower alkylamino group or di(lower)alkylamino group,
R8 is hydrogen atom, lower alkyl group, cycloalkyl group wherein said cycloalkyl group is optionally substituted by lower alkyl group or carboxy group,
carboxy group, lower alkoxycarbonyl group, aryl group, heteroaryl group wherein said aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group
wherein said lower alkyl group is optionally substituted by halogen atom,
hydroxy group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group,
aralkyl group
wherein said aralkyl group is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, haloalkyl group, cyano group, nitro group, amino group and acyloxy group,
or 5 to 7-membered saturated heterocycle having at least one nitrogen atom,
Y1 is oxygen atom, xe2x80x94NHxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NR12xe2x80x94
wherein R12 is lower alkyl group or xe2x80x94Y6 xe2x80x94R13 
wherein R13 is hydrogen atom, lower alkyl group or aryl group wherein said lower alkyl group or aryl group is optionally substituted by carboxy group, lower alkoxycarbonyl group or aralkyloxycarbonyl group, Y6 is xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94COCO2xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SO2(CH2)rxe2x80x94 or xe2x80x94(CH2)rxe2x80x94 wherein r is 0 or an integer of 1 to 3,
or a single bond,
Y2 is oxygen atom, sulfur atom or a single bond,
Y3 is 
xe2x80x83wherein s and t are the same or different and each is an integer of 1 to 3,
or a single bond,
Y4 is oxygen atom, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or a single bond,
Y5 is xe2x80x94(CH2)pxe2x80x94, xe2x80x94(CH2)pxe2x80x2xe2x80x94CHAkxe2x80x94(CH2)pxe2x80x3xe2x80x94, xe2x80x94(CH2)pxe2x80x2xe2x80x94CAkAkxe2x80x2xe2x80x94(CH2)pxe2x80x3xe2x80x94, 
xe2x80x83wherein Ak, Akxe2x80x2 are the same or different and each is lower alkyl group, p
is 0 or an integer of 1 to 3, pxe2x80x2 and pxe2x80x3 are the same or different and each is
0 or an integer of 1 or 2, or a single bond, ring A is 
xe2x80x83wherein R14 is carboxy group, lower alkoxycarbonyl group or
aralkyloxycarbonyl group
wherein said aralkyloxycarbonyl group is optionally substituted by halogen atom, nitro group, alkyl group, alkoxy group or trifluoromethyl group,
j is 1 or 2,
k is 0 or 1, and
m and n are the same or different and each is 0 or an integer of 1 to 3; and R1, R2 and R3 are the same or different and each is hydrogen atom, hydroxy group, lower alkyl group or aryl group, or a salt thereof or a prodrug thereof.
(2) The amidine compound of the formula [I] described in (1) above, wherein R is a group of the formula 
wherein R4, R5, R6, X2, X3, X4, X5, j and k are as defined above,
or a salt thereof or a prodrug thereof.
(3) The amidine compound of the formula [I] described in (2) above, wherein R is a group of the formula 
wherein R4, R5, R6, X2, X3, X4, X5, j and k are as defined above,
or a salt thereof or a prodrug thereof.
(4) The amidine compound of the formula [I] described in (3) above, wherein R is a group of the formula 
wherein R4, R5, R6, X2, X3, X4, X5, j and k are as defined above,
or a salt thereof or a prodrug thereof.
(5) The amidine compound of the formula [I] described in (4) above, wherein X3 is xe2x80x94(CH2)mxe2x80x94 wherein m is as defined above and X4 is a group of the formula 
and j is 1,
or a salt thereof or a prodrug thereof.
(6) The amidine compound of the formula [I] described in (5) above, wherein R6 is hydrogen atom, X2 is oxygen atom, and X5 is a single bond,
or a salt thereof or a prodrug thereof.
(7) The amidine compound of the formula [I] described in (1) above, wherein R is a group of the formula 
wherein R7, R8, Y1, Y2, Y3, Y4, Y5, ring A, m and n are as defined above,
or a salt thereof or a prodrug thereof.
(8) The amidine compound of the formula [I] described in (7) above, wherein ring A is a group of the formula 
or a salt thereof or a prodrug thereof.
(9) The amidine compound of (1) above, which is selected from the group consisting of
7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(quinolin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
N-methyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine oxime,
N-phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid methyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyrimidin-4-yl)piperidine-4-carboxylic acid,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-[N-[5-amidino-1-(1-phenylethylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]carbamoyl]benzoic acid,
4-[N-[5-amidino-1-(4-benzyloxyphenylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]carbamoyl]benzoic acid,
2-[4-(pyrrolidin-3-yloxy)phenoxymethyl]-1-(2-methoxyethyl)benzimidazole-5-carboxamidine,
2-[4-(1-acetimidoylpyrrolidin-3-yloxy)phenoxymethyl]-1-(2-methoxyethyl)-benzimidazole-5-carboxamidine,
7-[1-(2-hydroxyethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(pyridin-4-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-hydroxy-2-phenylethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid N-methylamide,
7-(1-acetylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-(1-benzylsulfonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-naphthylsulfonyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-(1-acetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-(1-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]acetamide,
N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]benzamide,
3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester,
4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester,
4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid,
6-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
1-[2-(benzothiazol-2-yl)-2-oxyethyl]-2-phenoxymethylbenzimidazole-5-carboxamidine,
trans-4-[2-[4-(1-acetimidoylpiperidin-4-yloxy)phenoxymethyl]-5-amidinobenzimidazol-1-ylacetylaminomethyl]cyclohexanecarboxylic acid,
trans-4-[2-[4-(1-acetimidoylpiperidin-4-yloxy)phenoxymethyl]-5-(N-methylamidino)benzimidazol-1-ylacetylaminomethyl]cyclohexanecarboxylic acid,
trans-4-[2-[4-(1-acetimidoylpiperidin-4-yloxy)phenoxymethyl]-5-[amino-(hydroxyimino)methyl]benzimidazol-1-ylacetylaminomethyl]cyclohexanecarboxylic acid,
2-[4-(piperidin-4-yloxy)phenoxymethyl]-1-phenacylbenzimidazole-5-carboxamidine,
2-[4-(1-acetimidoylpiperidin-4-yloxy)phenoxymethyl]-1-phenacylbenzimidazole-5-carboxamidine,
2-[2-[4-ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-yl]ethyl]-1-(cyclohexylcarbamoylmethyl)benzimidazole-5-carboxamidine,
4-[2-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-yl]ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
1-(cyclohexylcarbamoylmethyl)-2-[N-[1-(pyridin-4-yl)piperidin-4-yl]-N-ethoxalylaminomethyl]benzimidazole-5-carboxamidine,
N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[1-(pyridin-4-yl)piperidin-4-yl]aminooxalic acid,
2-[N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]-N-ethoxycarbonylmethyl-aminomethyl]-1-(cyclohexylcarbamoylmethyl)benzimidazole-5-carboxamidine,
N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]carbamoylbenzoic acid,
2-[N-[4-(1-amidinopiperidin-4-yloxy)phenyl]-N-(4-methoxycarbonylbenzoyl)-aminomethyl]-1-(cyclohexylcarbamoylmethyl)benzimidazole-5-carboxamidine,
N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-amidinopiperidin-4-yloxy)phenyl]carbamoylbenzoic acid,
N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]sulfamoylacetic acid,
7-[1-(pyridin-4-ylacetyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(3-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-hydroxybenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(pyridin-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylmethyl]indole-1-carboxylic acid methyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid benzyl ester,
N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carboxamide,
7-[1-(indol-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid,
N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetamide,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylaminoacetic acid,
7-[1-(5-nitropyridin-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-nitrobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-(1-hexaneimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide,
N-butyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide,
N-cyclohexyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-sulfonamide,
N-(2-nitrophenyl)-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-carbothioamide,
7-[1-(benzimidazol-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid ethyl ester,
3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxyymethyl)-1-(2-aminopyridin-5-ylcarbonyl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(3-aminopropionyl)-piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(imidazol-4-ylacetyl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(piperidin-4-ylsulfamoyl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-dimethylaminoacetylpiperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-3-ylcarbamoyl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-dimethylaminoacetylpiperidin-2-ylcarbonyl)piperidine-4-carboxylic acid ethyl ester,
4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-4-carboxypiperidin-1-yl]-1-methylpyridinium chloride,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(4-amidinophenyl)-piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid,
7-[2-(4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, and
4-(2-amidino-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, or a salt thereof or a prodrug thereof.
(10) The amidine compound of (3) above, which is selected from the group consisting of
7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(quinolin-4-yl)piperidin-4-ylnethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
N-methyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide oxime,
N-phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid methyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxyhc acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyrmidin-4-yl)piperidine-4-carboxylic acid,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
7-[1-(2-hydroxyethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(pyridin-4-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-hydroxy-2-phenylethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid N-methylamide,
7-(1-acetylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-(1-benzylsulfonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-naphthylsulfonyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-(1-acetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-(1-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]acetamide,
N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]benzamide,
3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester,
4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester,
4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid,
6-[1-(pyrdin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3 ,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
7-[1-(pyridin-4-ylacetyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(3-aminobenzyl)piperidin-4-ylmethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-hydroxybenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(pyridin-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylmethyl]indole-1-carboxylic acid methyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid benzyl ester,
N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carboxamide,
7-[1-(indol-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid,
N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetamide,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylaminoacetic acid,
7-[1-(5-nitropyridin-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-nitrobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-[1-(2-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
7-(1-hexaneidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide,
N-butyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide,
N-cyclohexyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-sulfonamide,
N-(2-nitrophenyl)-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carbothioamide,
7-[1-(benzimidazol-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid ethyl ester,
3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-aminopyridin-5-ylcarbonyl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(3-aminopropionyl)-piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(imidazol4-ylacetyl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(piperidin-4-ylsulfamoyl)piperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-dimethylaminoacetylpiperidine-4-carboxylic acid,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-3-ylcarbamoyl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-dimethylaminoacetylpiperidin-2-ylcarbonyl)piperidine-4-carboxylic acid ethyl ester,
4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-4-carboxypiperidin-1-yl]--methylpyridinium chloride,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(4-amidinophenyl)-piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid,
7-[2-(4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,
4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,
4-(2-amidino-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, and
4-(2-amidino-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,
or a salt thereof or a prodrug thereof.
(11) A pharmaceutical composition comprising an amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof, and a pharmaceutically acceptable additive.
(12) A blood coagulation inhibitor comprising an amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof as an active ingredient.
(13) A factor Xa inhibitor comprising an amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof as an active ingredient.
(14) An agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus, which comprises an amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof as an active ingredient.
(15) A method for inhibiting coagulation of blood, which comprises administering the amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof.
(16) A method for inhibiting factor Xa, which comprises administering the amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof.
(17) A method for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus, which comprises administering the amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof.
(18) Use of the amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof for the production of a blood coagulation inhibitor.
(19) Use of the amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof for the production of a factor Xa inhibitor.
(20) Use of the amidine compound of any of the above (1) to (10) or a salt thereof or a prodrug thereof for the production of an agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus.
(21) A commercial package comprising the blood coagulation inhibitor of the above (12) and a written matter associated therewith, the written matter stating that the inhibitor can or should be used for inhibiting coagulation of blood.
(22) A commercial package comprising the factor Xa inhibitor of the above (13) and a written matter associated therewith, the written matter stating that the inhibitor can or should be used for inhibiting factor Xa.
(23) A commercial package comprising the agent for the prophylaxis or treatment of the above (14) and a written matter associated therewith, the written matter stating that the agent can or should be used for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus.
The terms used in the present specification to explain the inventive compound are defined as follows.
xe2x80x9cLower alkyl groupxe2x80x9d is linear or branched alkyl group having 1 to 6 carbon atoms, which is exemplified by methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, tert-pentyl group, hexyl group and the like, with preference given to methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group and the like having 1 to 4 carbon atoms. Lower alkyl group at R13 is optionally be substituted by carboxy group, lower alkoxycarbonyl group or aralkyloxycarbonyl group.
xe2x80x9cCycloalkyl groupxe2x80x9d is alkyl having cyclic alkyl moiety having 3 to 10 carbon atoms. Examples thereof include cyclopropyl group, 2,3-dimethylcyclopropyl group, cyclobutyl group, 3-methylcyclobutyl group, cyclopentyl group 3,4-dimethylcyclopentyl group, cyclohexyl group, 4-methylcyclohexyl group, cycloheptyl group, cyclooctyl group, norbomyl group, adamantyl group, bicyclo[3.3.0]octan-1-yl group or bicyclo[3.3.1]nonan-9-yl group and the like. Preferred are cycloalkyl having 3 to 7 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. Cycloalkyl group at R8 is optionally substituted by lower alkyl group or carboxy group.
xe2x80x9cAlkylene group having 1 to 6 carbon atomsxe2x80x9d is linear or branched alkylene group having 1 to 6 carbon atoms, such as methylene group, ethylene group, propylene group, butylene group, pentylene group, hexylene group and the like, which is preferably methylene group, ethylene group, propylene group, butylene group and the like having 1 to 4 carbon atoms.
xe2x80x9cAlkenylene group having 2 to 6 carbon atomsxe2x80x9d is linear or branched alkenylene group having 2 to 6 carbon atoms, such as ethylene group, 1-propenylene group, 1-butenylene group, 2-butenylene group, 3-butenylene group, 1-pentenylene group, 2-pentenylene group, 3-pentenylene group, 1-hexenylene group, 2-hexenylene group, 3-hexenylene group, 4-hexenylene group, 5-hexenylene group and the like. Preferred are ethylene group, 1-propenylene group, 1-butenylene group, 2-butenylene group, 3-butenylene group and the like having 2 to 4 carbon atoms.
xe2x80x9cAryl groupxe2x80x9d is phenyl group, naphthyl group or biphenyl group having 6 to 12 carbon atoms, with preference given to phenyl group. Aryl group at R6 is optionally substituted by 1 to 3 substituents selected from lower alkyl group, hydroxy group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group. Aryl group at R8 is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group (said lower alkyl group is optionally substituted by halogen atom), hydroxy group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group. Aryl group at R13 is optionally substituted by carboxy group, lower alkoxycarbonyl group or aralkyloxycarbonyl group.
xe2x80x9cHeteroaryl groupxe2x80x9d is 5 or 6-membered aromatic ring having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and may form a condensed ring with other ring that may be partially saturated. Examples thereof include imidazolyl group, pyridyl group, pyridine-1-oxide group, pyrimidyl group, thienyl group, thiazolyl group, isoxazolyl group, oxadiazolyl group, triazolyl group, indolyl group, quinolyl group, furyl group, benzofuryl group, 1H-benzimidazolyl group, 2-benzothiazolyl group and the like. Preferred are pyridyl group, pyridine-1-oxide group, thienyl group, thiazolyl group, isoxazolyl group, indolyl group and the like. Heteroaryl group at R6 is optionally substituted by 1 to 3 substituents selected from lower alkyl group, hydroxy group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group. Heteroaryl group at R8 is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group (said lower alkyl group is optionally substituted by halogen atom), hydroxy group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group. The binding site of these heteroaryl groups is not limited as long as the site is chemically acceptable.
xe2x80x9cAralkyl groupxe2x80x9d is arylalkyl group wherein aryl moiety is as exemplified for the above-mentioned xe2x80x9caryl groupxe2x80x9d and alkyl moiety is as exemplified for the above-mentioned xe2x80x9clower alkyl groupxe2x80x9d, and is exemplified by benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, phenylhexyl group and the like. Aralkyl group may have, on the aryl group, 1 to 3 substituents selected from halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, haloalkyl group, cyano group, nitro group, amino group, acyloxy group and the like. It may be substituted simultaneously with two or more substituents, but preferably mono-substituted. The position of substitution is not particularly limited as long as it is chemically acceptable.
xe2x80x9cLower alkoxy groupxe2x80x9d is linear or branched alkoxy group having 1 to 6 carbon atoms and is exemplified by methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxy group, pentyloxy group, tert-pentyloxy group, hexyloxy group and the like. Preferred are methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxy group and the like having 1 to 4 carbon atoms.
xe2x80x9cLower alkoxycarbonyl groupxe2x80x9d is that wherein the lower alkoxy moiety is those exemplified for the above-mentioned xe2x80x9clower alkoxy groupxe2x80x9d. Examples thereof include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group and the like, with preference given to methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group and the like.
xe2x80x9cAralkyloxycarbonyl groupxe2x80x9d is that wherein the aralkyl moiety is those exemplified for the above-mentioned xe2x80x9caralkyl groupxe2x80x9d. Examples thereof include benzyloxycarbonyl group, 2-phenylethoxycarbonyl group, 3-phenylpropoxycarbonyl group and the like, which may be substituted by halogen atom, nitro group, alkyl group, alkoxy group, trifluoromethyl group and the like. Preferred is benzyloxycarbonyl group.
xe2x80x9cAcyl groupxe2x80x9d is formyl group; alkanoyl group having 2 to 6 carbon atoms such as acetyl group, propionyl group, butyryl group, pivaloyl group and the like; or aroyl group such as benzoyl group and the like wherein aryl group may have 1 to 3 substituents. Preferred are formyl group, acetyl group, pivaloyl group, benzoyl group and the like.
xe2x80x9cImidoyl groupxe2x80x9d is formimidoyl group, acetimidoyl group, propanimidoyl group, butanimidoyl group, pentaniimidoyl group or hexanimidoyl group and the like having 1 to 6 carbon atoms. Preferred are acetimidoyl group, propanimidoyl group and the like.
xe2x80x9cLower alkylamino groupxe2x80x9d is amino group monosubstituted by those exemplified to the above-mentioned xe2x80x9clower alkyl groupxe2x80x9d. Examples thereof include methylamino group, ethylamino group, propylamino group or butylamino group and the like, with preference given to methylamino group, ethylamino group, propylamino group and the like.
xe2x80x9cDi(lower)alkylamino groupxe2x80x9d is amino group disubstituted by those exemplified for the above-mentioned xe2x80x9clower alkyl groupxe2x80x9d, and is exemplified by dimethylamino group, diethylamino group, dipropylamino group, methylethylamino group, methylpropylamino group and the like. Preferred are dimethylamino group, diethylamino group and the like.
xe2x80x9cDi(lower)alkylamino(lower)alkanoyl groupxe2x80x9d is alkanoyl group substituted by those exemplified for the above-mentioned xe2x80x9cdi(lower)alkylamino groupxe2x80x9d. Examples thereof include dimethylaminoacetyl group, dimethylaminoacetyl group, dipropylaminoacetyl group, methylethylaminoacetyl group, methylpropylaminoacetyl group, dimethylaminopropanoyl group, diethylaminopropanoyl group, dipropylaminopropanoyl group and the like. Preferred are dimethylaminoacetyl group, diethylaminoacetyl group and the like.
xe2x80x9cAcylamino groupxe2x80x9d is amino group substituted by those exemplified for the above-mentioned xe2x80x9cacyl groupxe2x80x9d. Examples thereof include formylamino group; alkanoylamino group having 2 to 6 carbon atoms such as acetylamino group, propionylamino group, butyrylamino group, pivaloylamino group and the like; and aroylamino group such as benzoylamino group and the like, wherein aryl group may be substituted by 1 to 3 substituents. Preferred are formylamino group, acetylamino group, pivaloylamino group, benzoylamino group and the like.
xe2x80x9cHalogen atomxe2x80x9d is chlorine, bromine, fluorine or iodine, with preference given to chlorine or bromine.
xe2x80x9cSaturated 5- to 7-membered heterocycle having at least one nitrogen atomxe2x80x9d is exemplified by pyrrolidine, piperidine, hexahydroazepine, and oxazolidine, thiazolidine, imidazolidine, morpholine, thiomorpholine, piperazine, tetrahydrooxazepine, tetrahydrothiazepine, hexahydrodiazepine and the like having, as hetero atom, oxygen, sulfur and/or nitrogen atom. Saturated 5- to 7-membered heterocycle having at least one nitrogen atom at R6 may be substituted by lower alkyl group, acyl group, di(lower)alkylamino(lower)alkanoyl group or imidoyl group.
xe2x80x9cThe saltxe2x80x9d of the compound includes, but not limited to, inorganic acid addition salt such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate and the like; organic acid addition salt such as acetate, propionate, succinate, glycolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, ascorbate and the like; addition salt with amino acid such as aspartate, glutamate and the like; salt with inorganic base such as sodium, potassium, calcium, magnesium and the like; salt with organic base such as methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, triethanolamine, trishydroxymethylaminomethane, dicyclohexylamine, ethylenedimane, quinine, guanidine and the like; and base salt with amino acid such as asparagine, glutamine, arginine, histidine, lysine and the like. The salt may be water containing compound or hydrate.
xe2x80x9cThe prodrugxe2x80x9d of a compound is a derivative of the compound of the present invention, which has a chemically or metabolically degradable group and which shows pharmaceutical activity upon hydrolysis, solvolysis, or decomposition under physiolocial conditions.
xe2x80x9cVarious diseases caused by blood coagulation or thrombusxe2x80x9d include cerebrovascular deseases such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemia attack (TIA), subarachnoid hemorrhage and the like; ischemic heart diseases such as acute or chronic myocardial infarction, unstable angina, coronary thrombosis and the like; pulmonary vascular diseases such as pulmonary infarction, pulmonary embolism and the like; and diseases associated with various vascular disorders such as peripheral arterial embolism, deep vein thrombosis, disseminated intravascular coagulation, thrombosis after surgery of artificial blood vessels or replacement of artificial valve, reocclusion or restenosis after coronary bypass, reocclusion or restenosis after percutaneous transluminal coronary angioplasty (PICA) or percutaneous transluminal coronary recanalization (PIFCR), thrombosis due to extracorporeal circulation, and the like.
The compound of the present invention is explained in detail in the following.
Of the inventive compounds of the formula [I], R is a group of the formula 
and preferably a group of the formula 
and particularly preferably a group of the formula 
R1, R2 and R3 are preferably hydrogen atom.
The mode of connection of 
is preferably as shown by the formula 
Preferable R4 is hydrogen atom, lower alkoxy group or halogen atom, which is particularly preferably hydrogen atom. Preferable R5 is hydrogen atom, carboxy group or lower alkoxycarbonyl group, particularly preferably carboxy group. Preferable R6 is hydrogen atom, carboxy group, lower alkoxycarbonyl group, aryl group or heteroaryl group wherein aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from lower alkyl group, hydroxy group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group, which is particularly preferably pyridyl group.
Preferable X2 is oxygen atom or sulfur atom, which is particularly preferably oxygen atom. X3 is preferably xe2x80x94(CH2)mxe2x80x94, particularly preferably xe2x80x94(CH2)0xe2x80x94. X4 is preferably 
or a single bond, particularly preferably a single bond. X5 is preferably alkenylene group having 2 to 6 carbon atoms or a single bond, which is particularly preferably a single bond. Preferred j is 1, and k is preferably 0.
R7 is preferably 
wherein R9 is preferably oxygen atom or NH, and particularly preferably NH. R10 is preferably lower alkyl group, lower alkoxy group or amino group, and particularly preferably lower alkyl group or amino group. R8 is preferably hydrogen atom, aryl group, heteroaryl group wherein aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group (said lower alkyl group is optionally substituted by halogen atom), hydroxy group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group, particularly preferably phenyl group.
Y1 is preferably oxygen atom or xe2x80x94NR12xe2x80x94 wherein R12 is preferably xe2x80x94Y6xe2x80x94R13 wherein R13 is preferably phenyl group optionally substituted by carboxy group or lower alkoxycarbonyl group, Y6 is preferably xe2x80x94COxe2x80x94, particularly preferably xe2x80x94Nxe2x80x94Y6xe2x80x94R13. Y2 is preferably oxygen atom. Y3 is preferably 
wherein s and t are each preferably 2. Y4 is preferably xe2x80x94CONHxe2x80x94. Y5 is preferably xe2x80x94(CH2)pxe2x80x94, xe2x80x94(CH2)pxe2x80x2xe2x80x94CHAkxe2x80x94(CH2)pxe2x80x3xe2x80x94, xe2x80x94(CH2)pxe2x80x2xe2x80x94CAk Akxe2x80x2xe2x80x94(CH2)pxe2x80x3xe2x80x94 wherein p is preferably 1 or 2, pxe2x80x2 is preferably 1 and pxe2x80x3 is preferably 0, which is particularly preferably xe2x80x94(CH2)pxe2x80x2xe2x80x94CHAkxe2x80x94(CH2)pxe2x80x3xe2x80x94. The ring A is preferably a group of the formula 
The compound of the formula [I] of the present invention includes tautomer, stereoisomer, optical isomer and geometrical isomer. The present invention encompasses all of them.
The production method of the compound of the present invention is explained in the following, to which the production method of the inventive compound is not limited. 
The production method shown here is suitable for producing, of the compounds of the formula [I], compound of the formula [Ixe2x80x2]
In this case, connection between moieties [i], [ii], [iii], [iv] and [v] can be started from any position. Construction or conversion of each moiety may be carried out independently or may be done after connecting some moieties. When reactive functional group is present, a protecting group may be introduced or removed as appropriate.
[1] Connection of moiety [i] and moiety [ii]
A compound at the moiety [ii] of the formula (2) 
wherein 
means connection with other moiety or binding of a convertible group such as hydrogen atom, protecting group or leaving group and the like (hereinafter the same in the following formulas), and R4, X2, j and k are each as defined above, is reacted with the compound of the moiety [i] of the formula (3) 
wherein R1xe2x80x2, R2xe2x80x2 and R3xe2x80x2 are the same or different and each is hydrogen atom, hydroxy group, lower alkyl group, aryl group or a protecting group of nitrogen atom, or a salt thereof, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and the like to give a compound of the formula (4) 
wherein R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4, X2, j and k are each as defined above. When any of R1xe2x80x2, R2xe2x80x2 and R3xe2x80x2 is a protecting group, this protecting group can be removed by a conventional method.
Alternatively, ammonium thiocyanate and benzoyl chloride are reacted in advance under heating and a compound of the formula (2) is reacted to give a thioamide compound. Then, after treating with an acid such as hydrogen chloride, hydrogen bromide and the like, the compound is reacted with methyl iodide under heating, preferably at 50xc2x0 C.-70xc2x0 C. The compound may be reacted with amine having the desired substituent.
Alternatively, the compound of the formula (2) and the compound of the formula (5)
R1xe2x80x94NCSxe2x80x83xe2x80x83(5)
wherein R1 is as defined above, are reacted and then with methyl iodide to give thiomethyl compound, followed by reaction with ammonium acetate or amine having the desired substituent.
When a compound of moiety [ii] wherein j is 2 is desired, a compound of the formula (6) 
wherein Rh is a protecting group such as methyl group and the like, and R4, X2 and k are as defined above, is reacted with sodium azide and subjected to rearrangement reaction to give an azepinone compound. This compound is reduced with lithium aluminum hydride to give a compound of the formula (7) 
wherein R4, X2, Rh and k are as defined above.
[2] Connection or construction of moiety [ii] and moiety [iii]
A compound at the moiety [ii] of the formula (8) 
wherein R4, X2, j and k are as defined above, and a compound at the moiety [iii]of the formula (9) 
wherein L1 is leaving group such as halogen atom and the like or hydroxy and X3 is as defined above, are reacted to give a compound of the formula (10) 
wherein R4, X2, X3, j and k are as defied above. When L1 is a leaving group, it is subjected to alkylation using a base such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine and the like, and when L1 is hydroxy, it is subjected to Mitsunobu reaction using triphenylphosphine and diisopropyl azodicarboxylate.
When a compound wherein X2 is xe2x80x94SO2xe2x80x94 is desired, a compound of the formula (10) wherein X2 is sulfur atom is oxidized using a peracid such as m-chloroperbenzoic acid or peracetic acid and the like to give a compound of the formula (11) 
wherein R4, X3, j and k are as defined above.
When a compound wherein X2 is xe2x80x94SO2NHxe2x80x94 is desired, a compound of the formula (12) 
wherein R4, j and k are as defined above, and a compound of the formula (13) 
wherein X3 is as defined above, are subjected to typical amnidation under basic conditions to give a compound of the formula (14) 
wherein R4, X3, j and k are as defined above.
When a compound wherein k is 1 and X2 is oxygen atom is desired, a compound of the formula (15) 
wherein R4, Ak and j are as defined above is reduced using a reducing reagent such as sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride and the like to give a compound of the formula (16) 
wherein R4 and j are as defined above. The resultant compound is condensed with a compound of the formula (9) by the method shown in the production method of a compound of the formula (10) to give a compound of the formula (17) 
wherein R4, X3 and j are as defined above.
[3] Connection or construction of moiety [iii] and moiety [iv]
When a compound wherein R5 is hydrogen atom and X3 is xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)3xe2x80x94 is desired, the formula (18) 
wherein mxe2x80x2 is 0 or an integer of 1 or 2 and Ak is as defined above, is reduced using a reducing reagent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride and the like to give a compound of the formula (19) 
wherein mxe2x80x3 is an integer of 1 to 3.
Alternatively, a compound of the formula (20) 
wherein mxe2x80x2 is as defined above, is reduced using a reducing reagent such as borane and the like to give a compound of the formula (19). This compound corresponds to a compound of the formula (9) wherein X3 is xe2x80x94(CH2)mxe2x80x3xe2x80x94 and L1 is hydroxy group.
When a compound wherein R5 is cyano group, lower alkoxycarbonyl group or carboxy group and X3 is xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)3xe2x80x94 is desired, a compound of the formula (21) 
wherein R5xe2x80x2 is cyano group, lower alkoxycarbonyl group or carboxy group, is reacted with a compound of the formula (22)
L2xe2x80x94(CH2)mxe2x80x2xe2x80x94CHxe2x95x90CH2xe2x80x83xe2x80x83(22)
wherein L2 is a leaving group such as halogen atom and the like and mxe2x80x2 is as defined above, in the presence of a base such as lithium diisopropylamide and the like at xe2x88x9280xc2x0 C. to 0xc2x0 C. to give a compound of the formula (23) 
wherein R5xe2x80x2 and mxe2x80x2 are as defined above. The obtained compound is reacted with an oxidizing reagent such as osmium tetroxide and the like to give a diol compound wherein the double bond was oxidized. This diol compound is subjected to periodate oxidation to allow adjacent diol to be oxidatively cleaved to give an aldehyde compound. This is reduced using a reducing reagent such as sodium borohydride, lithium borohydride, sodium cyanoborohydride and the like to give a compound of the formula (24) 
wherein R5xe2x80x2 and mxe2x80x3 are as defined above. This compound corresponds to a compound of the formula (9) wherein X3 is xe2x80x94(CH2)mxe2x80x3xe2x80x94 and L1 is hydroxy group.
Alternatively, a compound of the formula (23) is subjected to periodate oxidation to give a carboxylic acid, which is reduced with a reducing reagent such as borane and the like to give a compound of the formula (24).
Alternatively, a compound of the formula (21) and a compound of the formula (25) 
wherein L2 and m are as defined above, may be reacted in the presence of a base such as lithium diisopropylamide and the like at xe2x88x9280xc2x0 C. to 0xc2x0 C.
When a compound wherein R5 is cyano group is desired, a compound of the formula (26) 
is amidated and reacted using a dehydrating reagent such as triphenylphosphine and the like to give a compound of the formula (27) 
Then, this compound may be bonded with a compound of moiety [iii] by a method similar to the production method of a compound of the formula (23) or a known method.
The leaving group L2 can be introduced into a compound of the formula (25) by, for example, a compound of the formula (28) 
wherein m is as defined above is reacted with a halogenation reagent such as sulfuryl chloride and the like to give a compound of the formula (25). The compound of the formula (25) may be converted to a compound with a leaving group having higher reactivity by the use of alkai metal halide.
When a compound wherein X2 is xe2x80x94SO2NHxe2x80x94 and X3 is xe2x80x94(CH2)mxe2x80x94 is desired, a compound of the formula (29) 
wherein R5 and m are as defined above, is subjected to Curtius rearrangement, Hofmann rearrangement and the like to give a carbamate compound, which is subjected to typical removing reaction of amino group to give a compound of the formula (30) 
wherein R5 and m are as defined above. This compound corresponds to a compound of the formula (13) wherein X3 is xe2x80x94(CH2)mxe2x80x94.
Alternatively, a compound of the formula (31) 
is subjected to Strecker reaction by reacting hydrogen cyanide in the presence of ammonia to give a compound of the formula (32) 
This compound corresponds to a compound of the formula (30) wherein R5 is cyano group and m is 0. Subsequent alcoholysis gives a compound of the formula (33) wherein R5 of the formula (30) is lower alkoxycarbonyl 
wherein Ak is as defined above, and hydrolysis of the resultant compound gives a compound of the formula (34) wherein R5 of the formula (30) is carboxy group 
[4] Connection or construction of moiety [iv] and moiety [v]
A compound at the moiety [iv] of the formula (35) 
wherein R5 is as defined above, is reacted with a compound at the moiety [v] of the formula (36)
L2xe2x80x94X4xe2x80x94X5xe2x80x94R6xe2x80x83xe2x80x83(36)
wherein R6, X4, X5 and L2 are as defined above, in the presence of a base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, N,N-diisopropylethylamine, pyridine and the like or reacted using a base such as triethylamine, N,N-diisopropylethylamine and the like at 120-160xc2x0 C. to give a compound of the formula (37) 
wherein R5, R6, X4 and X5 are as defined above.
When a compound wherein R6 is aryl group or heteroaryl group and the aryl group or heteroaryl group is substituted by amino group or acylamino group is desired, a compound having nitro group as a substituent at aryl group or heteroaryl group is reduced to give a compound having amino as a substituent. Further, an acylation reagent such as acyl halide, acid anhydride and the like is reacted to give a compound having of acylamino group as a substituent.
When a compound wherein X5 is xe2x80x94CHxe2x95x90CHxe2x80x94 is desired, a compound of the formula (38) 
wherein X4 is as defined above, is reacted with a compound of the formula (39) 
wherein R6 and Ak are as defined above, in the presence of a base such as sodium hydride, potassium hydride and the like, to give a compound of the formula (40) 
wherein R6 and X4 are as defined above. 
The production method shown here is suitable for producing, of the compounds of the formula [I], a compound of the formula [Ixe2x80x3]
In this case, connection between moieties [i], [iii], [iv], [v] and [vi] can be started from any position. Construction or conversion of each moiety may be carried out independently or may be done after connecting some moieties. When reactive functional group is present, a protecting group may be introduced or removed as appropriate.
[5] Connection and construction of moiety [i] and moiety [vi]
A compound at the moiety [vi] of the formula (41) 
wherein R4, X2 and k are as defined above, is reacted with a sulfonylation reagent such as trifluoromethanesulfonic anhydride and the like to convert hydroxy group thereof to a leaving group and reacted with cyanation reagent such as zinc cyanide and the like in the presence of a catalyst such as tetrakis-(triphenylphosphine)palladium and the like to give a cyano compound. The resultant compound is reacted with hydrogen sulfide under basic conditions to give a thioamide compound, which is further S-alkylated with methyl iodide and the like and reacted with ammonium acetate or amine having a desired substituent to give a compound of the formula (42) 
wherein R1, R2, R3, R4, X2 and k are as defined above.
When a compound of the formula (43) having halogen atom at the 8-position at R4
wherein Hal is halogen atom, and X2 and k are as defined above, is desired, a compound of the formula (44) 
wherein X2 and k are as defined above is halogenized with a halogenizing reagent such as tert-butyl hypochlorite and the like.
Connection of moiety [vi] and moiety [iii], and moiety [iii]-moiety [v] can be carried out in the same manner as in the connection of moiety [ii]-moiety [v] shown in Production Method 1. 
The production method shown here is suitable for producing, of the compounds of the formula [I], a compound of the formula [Ixe2x80x2xe2x80x3]
In this case, connection between moieties [i], [vii], [viii], [ix], [x] and [xi] can be started from any position. Construction or conversion of each moiety may be carried out independently or may be done after connecting some moieties. When reactive functional group is present, a protecting group may be introduced or removed as appropriate.
[6] Connection and construction of moiety [i] and moiety [vii]
Using a compound of the formula (45) 
and connection or construction of moiety [i] and moiety [vi] as shown in Production Method 2 is carried out to give a compound of the formula (46) 
wherein R1, R2, R3 are each as defined above.
[7] Connection and construction of moiety [vii] and moiety [viii], moiety [xi]
A compound of the formula (47) 
wherein L2 is as defined above, is reacted with a compound at the moiety [xi] of the formula (48)
H2Nxe2x80x94(CH2)nxe2x80x94Y4xe2x80x94Y5xe2x80x94R8xe2x80x83xe2x80x83(48)
wherein R8, Y4, Y5 and n are each as defined above, or a salt thereof, in the presence of a base such as triethylamine, N,N-diisoropylethylamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate and the like to give a compound of the formula (49) 
wherein R8, Y4, Y5 and n are as defined above. The compound of the formula (48) itself may be used as a base.
The nitro group of a compound of the formula (49) is reduced by a known method to give a compound of the formula (50) 
wherein R8, Y4, Y5 and n are each as defined above, and reacted with a compound of moiety [viii] of the formula (51) 
wherein m is as defined above, to give a compound of the formula (52) 
wherein R8, Y4, Y5, m and n are as defined above.
Alternatively, a compound of the formula (53) 
and a compound of the formula (51) are reacted to give a compound of the formula (54) 
wherein m is as defined above. This reaction can be a typical amidation reaction. For example, a condensing reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (EDCxc2x7HCl), diphenylphosphorylazide or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) and the like is used, or mixed acid anhydride method using alkylhalocarbonate and the like, or after conversion of carboxylic acid to acid halide using thionyl chloride, oxalyl chloride and the like, reaction under basic conditions, or other method may be used.
A compound of the formula (55) 
wherein Rhxe2x80x2 is a protecting group such as methyl group, ethyl group and the like and m is as defined above, is deprotected by a conventional method to give a compound of the formula (51). Alternatively, a compound of the formula (56) 
wherein m is as defined above, is oxidized by a typical method to give a compound of the formula (51).
A compound of the formula (52) and a compound of the formula (54) are subjected to ring-closing reaction under acidic conditions using acetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like to give a compound of the formula (57) 
wherein R8, Y4, Y5, m and n are as defined above, or a compound of the formula (58) 
wherein m is as defined above, respectively.
Alternatively, a compound of the formula (59) 
is converted to imidate using an alkoxide, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, and reacted with a compound of the formula (50) or a compound of the formula (53) under acidic conditions to give a compound of the formula (57) or a compound of the formula (58), respectively.
When a compound wherein Y4 is CONHxe2x80x94 is desired, a compound of the formula (60) 
wherein n is as defined above, and a compound of the formula (61)
H2Nxe2x80x94Y5xe2x80x94R8xe2x80x83xe2x80x83(61)
wherein R8 and Y5 are as defined above, are reacted in the same manner as shown in the production method of a compound of the formula (52) or a compound of the formula (54), to give a compound of the formula (62) 
wherein R8, Y5 and n are as defined above.
When a compound wherein Y4 is oxygen atom, Y5 is a single bond and R8 is lower alkyl group is desired, a compound of the formula (63) 
wherein n is as defined above, and a compound of the formula (64)
L1xe2x80x94R8xe2x80x2xe2x80x83xe2x80x83(64)
wherein R8xe2x80x2 is lower alkyl group and L1 is as defined above, are reacted in the same manner as shown in the production method of a compound of the formula (37) to give a compound of the formula (65) 
wherein R8xe2x80x2 and n are as defined above.
When a compound wherein Y4 is xe2x80x94COxe2x80x94, Y5 is a single bond and R8 is heteroaryl group is desired, a compound of the formula (60) is reacted with N,O-dimethylhydroxylamine in the same manner as shown in the production method of a compound of the formula (52) or a compound of the formula (54) to give a compound of the formula (66) 
wherein n is as defined above. Separately, a compound of the formula (67)
Hxe2x80x94R8xe2x80x3xe2x80x83xe2x80x83(67)
wherein R8xe2x80x3 is heteroaryl group is activated with a base such as butyl lithium and the like and reacted with the above-mentioned compound (66) to give a compound of the formula (68) 
wherein R8xe2x80x3 and n are as defined above.
[8] Connection and construction of moiety [viii] and moiety [ix]
A compound at the moiety [viii] of the formula (69) 
wherein L2 and m are as defined above, is reacted with a compound of the formula (70) 
wherein Y1 and ring A are as defined above, in the presence of a base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, N,N-diisopropylethylamine, pyridine and the like to give a compound of the formula (71) 
wherein Y1, ring A and m are each as defined above.
When a compound wherein Y1 is NH is desired, the compound is protected with a protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl and the like and subjected to the reaction and deprotected to give a compound of the formula (72) 
wherein ring A and m are as defined above. In addition, when a compound wherein Y1 is xe2x80x94NR12xe2x80x94 is desired, a compound of the formula (72) is reacted with a compound of the formula (73)
L2xe2x80x94R12xe2x80x83xe2x80x83(73)
wherein R12 and L2 are as defined above, in the same manner as in the production method of a compound of the formula (49) to give a compound of the formula (74) 
wherein R12 and m are as defined above.
When a compound wherein R12 is xe2x80x94Y6xe2x80x94R13, Y6 is xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94COCO2xe2x80x94 or xe2x80x94SO2xe2x80x94 is desired, a compound of the formula (72) is reacted with a compound of the formula (75)
HOxe2x80x94Y6xe2x80x2xe2x80x94R13xe2x80x83xe2x80x83(75)
wherein Y6xe2x80x2 is xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94COCO2xe2x80x94 or xe2x80x94SO2xe2x80x94 and R13 is as defined above, in the same manner as in the production method of a compound of the formula (52) or the formula (54) to give a compound of the formula (76) 
wherein R13, Y6xe2x80x2, ring A and m are as defined above.
When a compound wherein Y1 is a single bond and the ring A is a group of the formula 
is desired, a compound of the formula (77) 
wherein R14 is as defined above, and a compound of the formula (69) are reacted in the same manner as in the production method of a compound of the formula (23) to give a compound of the formula (78) 
wherein R14 and m are as defined above.
When a compound wherein Y1 is oxygen atom is desired, a compound of the formula (79) 
wherein ring A is as defined above, is oxidized with peracid such as m-chloroperbenzoic acid, peracetic acid and the like to give a compound of the formula (80) 
wherein ring A is as defined above. This compound corresponds to a compound of the formula (70) wherein Y1 is oxygen atom.
[9] Connection and construction of moiety [ix] and moiety [x]
A compound at the moiety [ix] of the formula (81) 
wherein Y1, L1 and ring A are as defined above, is reacted with a compound of the formula (82)
Hxe2x80x94Y2xe2x80x94Y3xe2x80x94R7xe2x80x83xe2x80x83(82)
wherein R7, Y2 and Y3 are as defined above, in the same manner as in the production method of a compound of the formula (10) to give a compound of the formula (83) 
wherein R7, Y1, Y2, Y3 and ring A are as defined above.
When a compound wherein ring A has the following formula 
and Y2 is a single bond, is desired, a compound of the formula (84) 
wherein Y1 is as defined above, or a compound of the formula (85) 
wherein R14 and Y1 are as defined above, is reacted with a compound of the formula (86)
L2xe2x80x94Y3xe2x80x94R7xe2x80x83xe2x80x83(86)
wherein R7, Y3 and L2 are as defined above, in the same manner as in the production method of a compound of the formula (37) to give a compound of the formula (87) 
wherein R7, Y1 and Y3 are as defined above, or a compound of the formula (88) 
wherein R7, R14, Y1 and Y3 are as defined above.
When a compound wherein Y3 is a group of the formula 
and R7 is lower alkyl group or 
is desired, a compound of the formula (89) 
wherein Y2, s and t are as defined above, is reacted with a compound of the formula (90)
L3xe2x80x94R7xe2x80x2
wherein L3 is a leaving group such as ethoxy group, 1-pyrazolyl group, halogen atom and the like and R7xe2x80x2 is lower alkyl group or a group of the formula 
wherein R9 and R10 are as defined above, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride and the like to give a compound of the formula (91) 
wherein R7, Y2, s and t are as defined above.
The compound of the formula [I] of the present invention thus obtained has a factor Xa inhibitory action. When the inventive compound is used as a factor Xa inhibitor or anti-blood coagulation agent, it is generally administered orally or parenterally and systemically or locally.
While the dose varies depending on the age, body weight, symptom, therapeutic effect, administration route, treatment time and the like, it is generally from 0.01 mg to 1 g for an adult, which is orally or parenterally administered once to several doses per day.
When the compound of the present invention is formulated into solid compositions for oral administration, it can be prepared into a dosage form such as tablet, pill, powder, granule and the like. In such solid compositions, one or more active substances are admixed with at least one inert diluent, dispersing agent or absorbent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystralline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate and anhydrous silicate powder. Moreover, the composition may comprise additives other than the diluent according to a conventional method.
When the compound is formulated into tablet or pill, gastric coating or enteric coating of, for example, sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate may be applied, or two more layers may be formed. Moreover, a capsule made from a substance such as gelatin and ethylcellulose may be used.
When a liquid composition for oral administration is desired, the compound can be formulated into a dosage form such as pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir and the like. Examples of diluent to be used include purified water, ethanol, vegetable oil and emulsifier. This composition may also comprise, besides the diluent, auxiliary agents such as wetting agent, suspending agent, sweetener, flavor, aromatic and preservative.
When the compound is prepared into an injection for parenteral administration, a sterile aqueous or nonaqueous solution, solubilizer, suspending agent or emulsifier is used. Examples of the aqueous solution, solubilizer and suspending agent include distilled water for injection, physiological saline, cyclodextrin and its derivatives, organic amines such as triethanolamine, diethanolamine, monoethanolamine, triethylamine, and inorganic alkaline solution.
When the compound is prepared into an aqueous solution, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and the like may be used. As the solubilizer, for example, polyoxyethylene hydrogenated castor oil, surfactants such as sucrose fatty acid ester (forming mixed micelle), lecithin and hydrogenated lecithin (forming liposome) may be used. In addition, an emulsion preparation comprising a nonaqueous solvent such as vegetable oil, and lecithin, polyoxyethylene hydrogenated castor oil, or polyoxyethylene polyoxypropylene glycol may be produced.
As other composition for parenteral administration, an external liquid, liniment such as ointment, suppository or pessary comprising one or more active ingredients, which can be formulated by a method known in this field of the art, may be employed.